Trying to Kill AIDS Virus By Luring It Out of Hiding

By DONALD G. McNEIL Jr.

Published: September 23, 2003

That evil is the AIDS virus, which has the power to hibernate, virtually forever, even in patients taking their triple-therapy cocktails with religious devotion.

Many AIDS specialists are working on ways to tease the virus out of hiding so it can be killed, and real progress has been made. A laboratory at the University of California at Los Angeles recently reported 80 percent success in mice.

Even that, however, cannot stop the virus from roaring back. ''Eighty percent is close,'' said Dr. Roger J. Pomerantz, an AIDS researcher at Thomas Jefferson University in Philadelphia. ''But close only counts in horseshoes and hand grenades.''

Even if the virus, battered by the combination punching of antiretroviral therapy, is found in just one dormant T cell in a million, repeated tests in humans have shown that it will re-emerge if the therapy stops.

Simply hunting it is a ticklish business, because the virus hides in the same memory T cells that act as triggers for the immune system. Failing to ''light up'' the virus in them will keep it hidden. But activating too many T cells means a cascade of immune reactions like those in toxic shock syndrome, possibly killing the patient.

Since beginning their quest 19 years ago with the realization that infected T cells somehow slept in ''reservoirs'' in the lymph glands, blood and perhaps in parts yet unknown, researchers have experimented with immune-boosting drugs borrowed from cancer therapy and with tiny ''smart bombs'' that use antibodies to hunt for one cell among billions and kill it with a minuscule dose of poison.

Despite regular advances, some prominent AIDS researchers worry that the task may be hopeless.

''It's a very, very, very difficult situation,'' Dr. Anthony S. Fauci, director of the National Institute of Allergy and Infectious Diseases, said. ''You can get a reservoir down to an undetectable level, and then if someone gets even a little blip of viremia, it can reseed the area, and you're back to Square 1.''

That ''blip of viremia,'' a jump in virus circulating in the bloodstream, can be set off even by a bout of flu or a rusty nail, because the AIDS virus can hide in a T cell that normally attacks the flu virus or tetanus.

Dr. Robert C. Gallo, director of the Institute of Human Virology at the University of Maryland, said many labs had attacked latent virus, with no breakthrough success yet.

The newest work, at U.C.L.A.'s AIDS Institute, was in mice bred without immune systems in which human thymus cells were implanted and infected. Although he praised the research, Dr. Gallo said the mouse-thymus model was ''a very artificial system.''

''If you had this in a monkey model, with demonstrable safety data,'' he said, ''that would merit highlighting it.''

The U.C.L.A. team, led by Dr. Jerome A. Zack and Dr. David G. Brooks, used interleukin-7 and prostratin to light up infected cells. If humans were given big enough doses to reach the most hidden cells, ''I don't know that it wouldn't be terribly dangerous,'' Dr. Gallo said.

The AIDS virus is frequently described as wily for its ability to mutate drug-resistant forms. But it is equally wily in its hibernation style, sitting as silent as a nuclear submarine on the ocean floor. Incorporated into the DNA of a shrunken, inactive T cell, the virus is a mere speck of genetic code, 10,000 base pairs out of the 6 billion in each human nucleus.

''It exists as pure information,'' Dr. Robert F. Siliciano, an AIDS researcher at the Johns Hopkins University, said. ''The immune system can't see it, because the system sees proteins, and it's not making proteins. The drugs don't touch it, because they stop replication, and it's not replicating.''

Dr. Siliciano recently demonstrated that the numbers of infected dormant cells remained steady over 7 years and might take 70 years to die off under normal antiretroviral assault. Trying to defeat that, researchers try ever more complicated regimens.

Dr. Fauci described treating 10 patients with multiple cycles of interleukin-2 to ''flush the virus out.''

''We thought the cells would spit out their virus and die, which would take care of those suckers, and then antiretrovirals would stop proliferation,'' he said.

After a moment of jubilation when he found no virus even in biopsies from his patients' lymph nodes, he went for ''the proof of the pudding'' and took the patients off their AIDS drugs.

''Everyone rebounded,'' he said. ''We failed.''

Mike Flanagan, 41, an architect, was in an even harsher pharmacological study led by Dr. Pomerantz. He was chosen, he said, because he knew the exact date when he was infected and was very good at taking his pills on time.

He was hospitalized to begin receiving a mix of eight AIDS and cancer drugs, including antiretrovirals, interleukin-2, hydroxyurea and OKT-3.

After another year as an outpatient, he was told to stop all drugs and wait.

In three months, ''it came back,'' he said, conceding disappointment. ''A lot of people put a lot of energy into that test, and I felt like I let them down. I thought there was a chance it would work.''

In the U.C.L.A. study, released last week by the journal Immunity, Dr. Zack described choosing his drugs -- prostratin and interleukin-7, to ''tickle the cell, just turn the virus on without turning on the cell.''

A ''turned-on'' virus, Dr. Zack explained, displays some of its proteins on the surface of the T cell, but does not prod the cell to divide or to wake up other T cells to begin an immune system assault on a foreign invader.

''Then we come in with the immunotoxin,'' he said. It is a molecule-size smidgen of bacterial poison attached to an antibody that gloms onto the T cell and injects the toxin.

Immunotoxins are too poisonous to use alone against AIDS, but they may work in combination with antiretrovirals, he said. If all goes well, he will try the tactic in monkeys and then humans.

But, Dr. Zack conceded, killing even 80 percent of the latent virus is probably not enough to finish the job. He may try more ''tickling'' drugs in combination or he may give the drugs in pulses. ''Maybe,'' he said, ''we can do better.''

Photo: Drs. Jerome A. Zack, right, and David G. Brooks of the U.C.L.A. AIDS Institute. (Photo by J. Emilio Flores for The New York Times) Chart/Diagram: ''Finding and Killing a Hidden Virus'' New therapies are being sought to destroy the latent AIDS virus in patients where it has been suppressed -- but not eliminated -- by drugs. PREPARATION -- The patient must already be doing so well on triple therapy that no replicating virus can be found in the bloodstream. Its progress has stopped, but the virus is not gone. LATENT VIRUS -- It is in hiding, incorporated into the DNA of helper T-cells in the lymph nodes, blood and perhaps elsewhere. Only one cell in a million may be infected. Because it is dormant, neither drugs nor the immune system can find it. DETECTION -- Immune-boosting drugs like interleukins tickle the T-cells into expressing small amounts of viral protein, betraying the virus inside. But turning on too many T-cells can cause a cascade of immune reactions, potentially harming the patient. KILLING -- An immunotoxin -- a bacterial poison attached to an antibody that recognizes the viral protein -- is injected. It attaches to the ''tickled'' cells and kills them. In mice, 80 percent were killed. But that may not be enough to prevent the infection from coming back if antiretroviral therapy is stopped. (Source by Dr. Jerome A. Zack, University of California, Los Angeles)(pg. F7)